This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Name
Foretinib
Accession Number
DB12307  (DB05030)
Type
Small Molecule
Groups
Investigational
Description

Foretinib has been used in trials studying the treatment of Cancer, Breast Cancer, Carcinoma, Renal Cell, Recurrent Breast Cancer, and Neoplasms, Head and Neck, among others. Foretinib is an orally available small molecule compound designed to target multiple RTKs implicated in the development, progression and spread of cancer. It inhibits the activation of MET, RON, ERK and AKT, decreased proliferation and increased apoptosis.

Structure
Thumb
Synonyms
Not Available
External IDs
EXEL-2880 / GSK-089 / GSK-1363089 / GSK-1363089G / GSK089 / GSK1363089 / GSK1363089G / XL-880 / XL880
Categories
UNII
81FH7VK1C4
CAS number
849217-64-7
Weight
Average: 632.6538
Monoisotopic: 632.24464125
Chemical Formula
C34H34F2N4O6
InChI Key
CXQHYVUVSFXTMY-UHFFFAOYSA-N
InChI
InChI=1S/C34H34F2N4O6/c1-43-30-20-25-27(21-31(30)45-16-2-13-40-14-17-44-18-15-40)37-12-9-28(25)46-29-8-7-24(19-26(29)36)39-33(42)34(10-11-34)32(41)38-23-5-3-22(35)4-6-23/h3-9,12,19-21H,2,10-11,13-18H2,1H3,(H,38,41)(H,39,42)
IUPAC Name
N-[3-fluoro-4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)phenyl]-1-[(4-fluorophenyl)carbamoyl]cyclopropane-1-carboximidic acid
SMILES
COC1=C(OCCCN2CCOCC2)C=C2N=CC=C(OC3=C(F)C=C(C=C3)N=C(O)C3(CC3)C(=O)NC3=CC=C(F)C=C3)C2=C1

Pharmacology

Indication
Not Available
Pharmacodynamics
Not Available
Mechanism of action

Activation of MET by mutation is the causative factor in an inherited kidney cancer syndrome, hereditary papilliary renal cell carcinaoma. Mutational activation of MET has also been found in sporadic kidney cancer, lung carcinomas and head and neck carcinomas. MET is a key driver of tumor cell growth, motility, invasion, metastasis and angiogenesis. Foretinib has attractive pharmaceutical properties with high solubility and oral bioavailability and demonstrates nanomolar potency against its targets, VEGFR, MET, which translates to potent activity in cellular assays. In preclinical studies, Foretinib, developed as a balanced inhibitor of these receptor tyrosine kinases, potently inhibited both MET and VEGFR, including mutant activated forms of MET found in hereditary papillary renal carcinomas. The compound also demonstrated dose-dependent growth inhibition in tumor models of breast, colorectal, non-small cell lung cancer and glioblastoma and has been shown to cause substantial tumor regression in all models tested.

TargetActionsOrganism
UHepatocyte growth factorNot AvailableHumans
UVascular endothelial growth factor receptor 2Not AvailableHumans
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
3,5-diiodothyropropionic acidThe therapeutic efficacy of 3,5-diiodothyropropionic acid can be decreased when used in combination with Foretinib.
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Foretinib.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Foretinib.
BenzylthiouracilThe therapeutic efficacy of Benzylthiouracil can be decreased when used in combination with Foretinib.
CarbimazoleThe therapeutic efficacy of Carbimazole can be decreased when used in combination with Foretinib.
DibromotyrosineThe therapeutic efficacy of Dibromotyrosine can be decreased when used in combination with Foretinib.
FollitropinThe therapeutic efficacy of Follitropin can be decreased when used in combination with Foretinib.
LevothyroxineThe therapeutic efficacy of Levothyroxine can be decreased when used in combination with Foretinib.
LiothyronineThe therapeutic efficacy of Liothyronine can be decreased when used in combination with Foretinib.
LiotrixThe therapeutic efficacy of Liotrix can be decreased when used in combination with Foretinib.
Food Interactions
Not Available

References

General References
Not Available
External Links
PubChem Compound
42642645
PubChem Substance
347828572
ChemSpider
24608641
BindingDB
50399540
ChEBI
91418
ChEMBL
CHEMBL1230609
HET
88Z
Wikipedia
Foretinib
PDB Entries
3lq8 / 5ia4 / 6i2y

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHepatocellular,Carcinoma1
1CompletedTreatmentSolid Tumor Cancers / Tumors, Solid1
1CompletedTreatmentTumors, Solid2
1, 2CompletedTreatmentCancer, Breast1
2CompletedTreatmentNeoplasms, Gastrointestinal Tract1
2CompletedTreatmentNeoplasms, Head and Neck / Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck1
2CompletedTreatmentRecurrent Breast Cancer1
2CompletedTreatmentRenal Cell Adenocarcinoma1
2WithdrawnTreatmentMalignancies1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00193 mg/mLALOGPS
logP4.5ALOGPS
logP3.18ChemAxon
logS-5.5ALOGPS
pKa (Strongest Acidic)4.59ChemAxon
pKa (Strongest Basic)6.88ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area114.74 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity169.05 m3·mol-1ChemAxon
Polarizability65.04 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Ethers
Direct Parent
Diarylethers
Alternative Parents
Quinolines and derivatives / Anilides / Anisoles / N-arylamides / Phenoxy compounds / Alkyl aryl ethers / Fluorobenzenes / Aryl fluorides / Morpholines / Cyclopropanecarboxylic acids and derivatives
show 13 more
Substituents
Diaryl ether / Quinoline / Anilide / Phenoxy compound / Anisole / Phenol ether / N-arylamide / Alkyl aryl ether / Halobenzene / Fluorobenzene
show 29 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Serine-type endopeptidase activity
Specific Function
Potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as a growth factor for a broad spectrum of tissues and cell types. Activating ligand for the rec...
Gene Name
HGF
Uniprot ID
P14210
Uniprot Name
Hepatocyte growth factor
Molecular Weight
83133.115 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and ...
Gene Name
KDR
Uniprot ID
P35968
Uniprot Name
Vascular endothelial growth factor receptor 2
Molecular Weight
151525.555 Da

Enzymes

Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...

Components:
References
  1. Singh RP, Patel B, Kallender H, Ottesen LH, Adams LM, Cox DS: Population pharmacokinetics modeling and analysis of foretinib in adult patients with advanced solid tumors. J Clin Pharmacol. 2015 Oct;55(10):1184-92. doi: 10.1002/jcph.546. Epub 2015 Jul 7. [PubMed:25998042]

Drug created on October 20, 2016 15:53 / Updated on November 02, 2018 07:23